A class of compounds that show promise by acting as class specific inhibitors of cysteine proteinase are L-trans-epoxysuccinyl peptides. One such peptide is the compoudn L-trans-epoxysuccinyl-L-leucylamido (e-guanidino) butane. This compound was shown to inhibit papain with the disappearance of the thiol group of papain and to inhibit cathepsin B, L, and H. By contrast, the serine proteinases and the indicated that L-trans-epoxysuccinyl-L-leucylamido (e-guanidino) butane inactivates cathepsin B and L by a stoichiometric reaction with the cystein residue essential for catalytic activity [Barrett et al., Biochem, J. (1982) 201, 189-198]. The kinetics of inhibition also show that the action of L-trans-epxoysuccinyl-L-leucylamido (e-guanidino) butane is not competitive with substrate and that the binding is irreversible by a covalent reaction at the active site. The inhibitor is selective due to the affinity of the inhibitors to the appropriate peptide components (dipeptide) for the specificity site of the proteinases.
Certain epoxysuccinyl amino acid derivatives, including L-trans-epoxysuccinyl-L-leucylamido (e-guanidino) butane, (known as E-64), are shown in U.S. Pat. No. 4,418,075 and the art cited therein. The compounds of U.S. Patent 4,418,075, however, are taught to be inhibitors of calcium-activated neutral thio protease useful in the treatment of muscular dystrophy. These same compounds are shown and by R. N. Mascardo and G. F. Eilon, J. Pharm. Exper. Therap., 244, 361-367, 1988, to be effective to promote endothelial cell migration to wounded areas.
Although epxoy succinyl amino acid derivatives are useful to achieve effects as taught, further compounds to achieve the same effects are desired, especially compounds which do not contain epoxy groups. Epoxy groups are alkylating agents and associated with cellulor toxicity.
Thus, it is a purpose of the present invention to produce N-(N-succinyl-L-leucyl)agmatine and related compounds.
It is further a purpose of the present invention to demonstrate the usefulness of such compounds in applications for which the epoxysuccinyl amino acids described above are known to be effective.